Preparation of compounds from levulinic acid

ABSTRACT

The present invention provides a method of making carboxylic acids from levulinic acid, such as succinic acid and 3-hydroxypropanoic acid, by reacting levulinic acid with an oxidant such as hydrogen peroxide under acidic or basic conditions.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/547,041, filed Jul. 27, 2017, which is the U.S. National Stage Entryunder § 371 of International Application No. PCT/US2016/015605, filedJan. 29, 2016, which claims priority to U.S. Provisional Application No.62/115,848, filed Feb. 13, 2015, and 62/109,787, filed Jan. 30, 2015,each of which is incorporated in its entirety herein for all purposes.

BACKGROUND OF THE INVENTION

Succinic acid (SA) is an organic chemical of major commercial potential.Although the current market for SA is limited by its comparatively highprice, it has been proposed as a feedstock for a variety of high-volumecommodity chemicals, including 1,4-butanediol (BDO), gamma-butyrolactone(GBL), maleic anhydride (MA), and tetrahydrofuran (THF), among others.The recent description of biodegradable polypropylene succinate in theform of a stereocomplex with properties comparable to LDPE may alsostimulate new commercial applications. SA is conventionally sourced viathe C₄ stream of the light naphtha raffinate of petroleum, usually byhydrogenation of MA or maleic acid, or oxidation of BDO, although thereare other approaches. Recently, however, a number of companies havebegun producing SA via fermentative pathways with the goal of becomingcompetitive with petrochemical routes, such that the global demand forSA has been predicted to increase from the current <100 kT to >700 kTper annum by 2020, representing a ca. $1B market.

The biological route to succinic acid is centered around nativeoverproducer bacteria and genetically engineered E. coli. Carbon sourcesare typically sugars, which may be derived from lignocellulosehydrolysates. Although generally good yields and productivity have beenreported, challenges associated with downstream processing, includingselectivity issues, the use of bases as neutralizing agents, and productisolation complicate the overall economics of the process.

In principle, chemical-catalytic pathways offer much faster and morescalable routes to SA from carbohydrates. Although no practical accessto SA directly from raw biomass has yet been developed, approaches viafurfural and levulinic acid, both one step removed from biomass, havebeen described. Thus, Choudhary et al. recently reported the oxidationof furfural, a derivative of hemicellulose, with H₂O₂ at 80° C. over 24hours to give SA in up to 74% yield. However, the SA was contaminatedwith a maleic acid by-product and the reaction is dependent on anultimately degradable catalyst (Amberlyst-15) (Chem. Lett. 2012, 41,409). Beyond this, the cost of the feedstock and long reaction periodgive little advantage over fermentative routes. Related methodsinvolving furfural and other furans using a range of oxidants andcatalysts generally give SA in lower yields and selectivities, and aredescribed in reviews.

Levulinic acid (LA) is a renewable feedstock of exceptional promise.Unlike furfural, LA can be derived both from hemicellulose and themajor, cellulosic fraction of carbohydrates. It can be produced in highyield via the acidic processing of biomass, and although this ispracticed commercially only on a limited scale at present, economicprojections have indicated that the production costs of LA could fall aslow as $0.04-$0.10/lb. LA can also be accessed in high yield by thehydrolysis of the biomass derived platform molecule5-(chloromethyl)furfural (CMF). As such, the potential of LA to unlockkey renewable markets is vast.

The conversion of LA to SA was first described in a paper by Tollens asearly as 1879. Nitric acid was employed as the oxidant, resulting in amixture of organic acids, including SA, albeit in low yield (Chem. Ber.1879, 12, 334). The first report of the action of hydrogen peroxide onLA was published in 1934, which described a reaction at 60° C. in thepresence of a cupric salt catalyst, again giving a mixture of carboxylicacids but only trace SA (Biochem. J. 1934, 28, 892). U.S. Pat. No.2,676,186 reported the gas phase oxidation of LA with O₂ and a vanadiumcatalyst at 375° C., wherein a maximum yield of 83% was claimed. Thisapproach might have been of preparative interest were not the conditionsso severe.

The current emphasis on green chemical production has led to a renewedinterest in the conversion of LA to SA, and a flurry of recentpublications describing this reaction has appeared. Thus, WO 2012/044168describes the heating of LA with nitric acid-NaNO₂ at 40° C. for 4 h togive mixtures of SA and oxalic acid, the former in up to 52% yield. Liuet al. reported the application of a Mn(III) catalyst in the oxidationof methyl levulinate at 90° C. under 5 bar of O₂ to give a mixture ofdimethyl succinate, malonate, and oxalate esters, along with relatedacetal derivatives (Chem Sus Chem 2013, 6, 2255). The maximum yield ofsuccinate was 52% in a 20 hour reaction. Podolean et al. employedRu(III) functionalized silica-coated magnetic nanoparticles under 10 barO₂ at 150° C. for 6 hours in the conversion of LA to SA, where catalystrecycling experiments demonstrated good reusability (×3) at conversionsof 54-58% and a 4% loading of ruthenium (Green Chem. 2013, 15, 3077).Finally, an interesting reaction was reported by Caretto and Perosa thatinvolved simple heating of LA in a dimethylcarbonate/base mixture at200° C. for 4 h to give dimethyl succinate among a range of otherproducts in up to 20% yield (Sustainable Chem. Eng. 2013, 1, 989).

What is needed is a process that overcomes the modest yields, poorselectivity, severe conditions, and/or potentially foulable catalysts inthe prior processes. Surprisingly, the present invention meets this andother needs.

3-Hydroxypropanoic acid (HPA) is considered a renewable target moleculeof enormous latent potential, due to the fact that it provides a directentry into the vast market for acrylic acid and its derivatives, whileat the same time unlocking the bio-compatible/degradable HPA homopolymermarket, which also shows much promise. The production of HPA frombiomass sources is described in the literature almost exclusively bymeans of fermentation of glucose or glycerol. Although advances havebeen made, particularly in the development of recombinant yeast asproducers, a number of technical hurdles remain, particularly associatedwith performance and downstream processing. HPA can also be produced viapetrochemical approaches which have generally involved the hydration ofacrylic acid or oxidation of allylic alcohol or propanediol, but currentinitiatives place a greater premium on the production of chemicaldrop-ins from renewable resources, rather than making biochemicals frompetroleum.

In principle, chemical-catalytic pathways offer much faster and morescalable routes to HPA from carbohydrates than fermentative approaches,and a straightforward opportunity for the production of HPA from biomassappeared to present itself in the selective oxidation of levulinic acid(LA). We reasoned that if the selectivity of the oxidation of LA to SAwith hydrogen peroxide could be reversed to favor the alternativemigration product, a complementary route to HPA would also beforthcoming. Surprisingly, the present invention provides the analogousconversion of LA into HPA using H₂O₂ under modified reaction conditions.

BRIEF SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a method of preparinga carboxylic acid, including forming a reaction mixture comprisinglevulinic acid, an oxidant, and an acid or a base, under conditionssuitable to prepare the carboxylic acid.

In another embodiment, the present invention provides a method ofpreparing succinic acid, including forming a reaction mixture comprisinglevulinic acid, an oxidant and an acid, thereby preparing the succinicacid.

In another embodiment, the present invention provides a method ofpreparing 3-hydroxypropanoic acid, including forming a reaction mixturecomprising levulinic acid, an oxidant, and a base, under conditionssuitable to form the 3-hydroxypropanoic acid.

In another embodiment, the present invention provides a method ofpreparing 3-hydroxypropanoic acid, including forming a reaction mixturecomprising levulinic acid, an oxidant, and a base, wherein the reactionmixture is at a temperature between about 75° C. and about 200° C.,thereby forming 3-hydroxypropanoic acid.

In another embodiment, the present invention provides a method ofpreparing 3-hydroxypropanoic acid, including forming a reaction mixturecomprising levulinic acid, an oxidant, and a base, wherein the reactionmixture is at a temperature between about 0° C. and about 50° C.,thereby forming 3-(hydroperoxy)propanoic acid, and forming a secondreaction mixture comprising the 3-(hydroperoxy)propanoic acid and ahydrogenation agent, under conditions suitable to form the3-hydroxypropanoic acid.

DETAILED DESCRIPTION OF THE INVENTION I. General

The present invention describes methods of preparing carboxylic acidsfrom biomass. For example, levulinic acid mixed with an oxidant such ashydrogen peroxide, and an acid or a base, is capable of preparingcommercially valuable compounds such as succinic acid and3-hydroxypropanoic acid. When an acid is combined with the levulinicacid and hydrogen peroxide, the carboxylic acid can be succinic acid.When a base is combined with the levulinic acid and hydrogen peroxide,the carboxylic acid can be 3-hydroxypropanoic acid. The3-hydroxypropanoic acid can be prepared directly from the levulinic acidwhen the reaction temperature is about 100° C. The 3-hydroxypropanoicacid can also be prepared at room temperature in a two-step process byfirst preparing 3-(hydroperoxy)propanoic acid, followed by reaction ofthe 3-(hydroperoxy)propanoic acid with a hydrogenation agent.

II. Definitions

“Forming a reaction mixture” refers to the process of bringing intocontact at least two distinct species such that they mix together andcan react, either modifying one of the initial reactants or forming athird distinct species, i.e., a product. It should be appreciated,however, that the resulting reaction product can be produced directlyfrom a reaction between the added reagents or from an intermediate fromone or more of the added reagents which can be produced in the reactionmixture.

“Acid” refers to a compound that is capable of donating a proton (H⁺)under the Bronsted-Lowry definition, or is an electron pair acceptorunder the Lewis definition. Acids useful in the present invention areBronsted-Lowry acids that include, but are not limited to, alkanoicacids or carboxylic acids (formic acid, acetic acid, citric acid, lacticacid, oxalic acid, etc.), sulfonic acids and mineral acids, as definedherein. Mineral acids are inorganic acids such as hydrogen halides(hydrofluoric acid, hydrochloric acid, hydrobromice acid, etc.), halogenoxoacids (hypochlorous acid, perchloric acid, etc.), as well as sulfuricacid, nitric acid, phosphoric acid, chromic acid and boric acid.Sulfonic acids include methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, triflouromethanesulfonic acid, camphorsulfonicacid, among others. Strong acid” refers to acids having a pK_(a)generally less than about 1.0. Representative strong acids include, butare not limited to, trifluoroacetic acid, triflic acid, methanesulfonicacid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, andnitric acid.

“Oxidant”, “oxidizing agent” or “oxidizer” all refer to any non-metalagent capable of oxidizing an organic compound, such as an alcohol to acarboxylic acid. Representative oxidants include, but are not limitedto, inorganic peroxides such as hydrogen peroxide, organic peroxidessuch as perbenzoic acid, nitric acid, sulfuric acid, and others. Theoxidant of the present invention does not include an oxidizing metalcatalyst, such as an oxidizing agent containing a metal such as anytransition metal. Representative transition metals include, but are notlimited to, chromium, manganese, ruthenium, vanadium or osmium.Representative oxidizing metal catalysts include, but are not limitedto, MnO₄ ⁻ (permanganate), CrO₄ ²⁻ (chromate), and OsO₄ (osmiumtetroxide).

“Base” refers to a compound capable of accepting a proton (H⁺) under theBronsted-Lowry definition, or is an electron-pair donor under the Lewisdefinition. Bases useful in the present invention that areBronsted-Lowry bases include hydroxides such as lithium hydroxide,sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesiumhydroxide, magnesium hydroxide, strontium hydroxide, barium hydroxide,and others. “Strong base” refers to bases having conjugate acids with apK_(a) generally greater than about 13.

“Room temperature” refers to a temperature of 20° C. to 25.5° C.

“Hydrogenation agent” refers to agents capable of the addition orinsertion of molecular hydrogen (H₂) or the donation of a hydride (H⁻).Representative hydrogenation agents include, but are not limited to,hydrogen gas plus a hydrogenation catalyst such as palladium on carbon(Pd/C), lithium aluminum hydride, sodium hydride, sodium borohydride,sodium cyanoborohydride, etc.

III. Method of Preparing a Carboxylic Acid

The present invention provides a method of preparing a carboxylic acidby combining levulinic acid, an oxidant, and an acid or a base. In someembodiments, the present invention provides a method of preparing acarboxylic acid, including forming a reaction mixture comprisinglevulinic acid and an oxidant, under conditions suitable to prepare thecarboxylic acid.

The carboxylic acid can be any suitable carboxylic acid. For example,the carboxylic acid can be a C₃₋₄ carboxylic acid. In some embodiments,the carboxylic acid has the formula:

wherein n is 0 or 1. In some embodiments n is 0. In some embodiments, nis 1. In some embodiments, the carboxylic acid is succinic acid or3-hydroxypropanoic acid.

The oxidant can be any suitable oxidant, other than an oxidizing metalcatalyst. In some embodiments, the oxidant can be hydrogen peroxide.

The reaction mixture is substantially free of an oxidizing metalcatalyst. Oxidizing metal catalysts can be manganese, chromium, osmium,ruthenium, and other metals.

In some embodiments, the present invention provides a method ofpreparing a carboxylic acid, including forming a reaction mixturecomprising levulinic acid, an oxidant, and an acid or a base, whereinthe reaction mixture is substantially free of an oxidizing metalcatalyst, under conditions suitable to prepare the carboxylic acid. Insome embodiments, the present invention provides a method of preparing acarboxylic acid, including forming a reaction mixture comprisinglevulinic acid, hydrogen peroxide, and an acid or a base, wherein thereaction mixture is substantially free of an oxidizing metal catalyst,under conditions suitable to prepare the carboxylic acid.

A. Preparation of Succinic Acid

In some embodiments, the carboxylic acid can be succinic acid. Succinicacid, also known as butanedioic acid, has the following structure:

Hydrogen peroxide is identified as a reagent for the oxidation of LA dueto its well-known Baeyer-Villiger type mechanism of action (Scheme 1).

Initial experiments with H₂O₂ in aqueous sulfuric acid showed promise,giving a mixture of SA (48%), acetic acid (50%), formic acid (24%), andmethanol (17%) (estimated yields by ¹H NMR integration). Considering thereaction in Scheme 1, methanol is an expected byproduct, and the strongoxidizing conditions also lead to the conversion of LA to acetic acid.This chemistry is precedented—in fact, WO 2013/159322 uses LA as afeedstock for producing acetic acid with a range of oxidants, includingH₂O₂. Formic acid is also seen in some cases as a byproduct. Theobservation of acetic acid can be explained as shown in Scheme 2 byinvoking the alternative migration product in the Baeyer-Villigeroxidation, i.e. 3-hydroxypropanoic acid (HPA), as an intermediate. Theconversion of LA to HPA co-produces a molecule of acetic acid onhydrolysis of the initially formed ester. HPA can then undergo a retroaldol cleavage (RA) to give acetic acid and formaldehyde, the latterultimately being oxidized to formic acid.

While the acetic acid, formic acid, and methanol are volatile and can beremoved from the reaction mixture, separation of the SA product fromaqueous sulfuric acid is difficult, and the recycle of sulfuric acid iscostly. A solution to these issues presented itself in the form oftrifluoroacetic acid (TFA) which, with pK_(a) of ca. 0, was found to besufficiently acidic to catalyze the reaction (Chem. Phys. Lett. 2008,451, 163). Thus, when a mixture of LA and 30% aqueous H₂O₂ in TFA washeated at 90° C., the starting material was consumed within 2 hours andthe result was a 62% yield of SA, alongside 43% acetic acid, 45% formicacid, and 9% HPA (estimated yields by ¹H NMR integration). The initiallyformed monomethyl ester of SA trans-esterifies with TFA to give methyltrifluoroacetate (45%), which is captured in a cold trap. The volatilepart of the reaction mixture thus consists of TFA methyl ester (bp 43°C.), TFA (bp 72° C.), the TFA-water azeotrope (79 wt % TFA, bp 105° C.)and finally acetic acid (bp 118° C.). The residual, white solid mass canbe triturated with ether, in which SA is largely insoluble, to give pureSA (60% isolated yield). A scaled up reaction starting with 10.0 g of LAprovided 6.0 g of SA (59%). The triturate includes HPA, a small amountof SA, and a mixture of unidentified, minor products.

The management of the TFA would be an important aspect of this processfrom an applied perspective. Taking the larger scale reaction(processing 10.0 g LA feedstock) as an example, the total 50 mL of 30%H₂O₂ used is capable of delivering a maximum of 48 g H₂O. The 200 mL ofTFA used corresponds to 298 g, of which 180 g will combine with the 48 gof H₂O to form 228 g of the azeotrope, with a remainder of 118 g TFA.While 30% aq H₂O₂ was used in this work, 50% H₂O₂ is generallyavailable, with industrial concentrations up to 70%. For the 50% and 70%grades, the delivery of less water with the same quantity of H₂O₂ wouldresult in the formation of 121 g and 76 g of the azeotrope,respectively, from which 25.5 and 16 g of water would need to beremoved. Recycling of TFA is accomplished by dehydration of theazeotrope by membrane pervaporation. The above reaction was performedusing 50% H₂O₂ with no significant variation in outcome.

In some embodiments, the method includes forming the reaction mixturecomprising levulinic acid, the oxidant and an acid, thereby preparingthe succinic acid. The reaction in the methods of the invention can beconducted at any suitable temperature. In general, reactions areconducted at temperatures ranging between about 20° C. and about 200° C.A reaction can be conducted, for example, at from about 20° C. to about100° C., or from about 30° C. to about 100° C., or from about 40° C. toabout 100° C., or from about 50° C. to about 100° C. A reaction can beconducted at about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, orabout 155° C. In some embodiments, the temperature can be about 90° C.

In some embodiments, the method includes forming the reaction mixturecomprising levulinic acid, the oxidant and an acid, and heating thereaction mixture at a temperature of from about 30° C. to about 100° C.,thereby preparing the succinic acid.

Any suitable non-metal oxidant can be used in the method of makingsuccinic acid. In some embodiments, the oxidant can be hydrogenperoxide.

Any suitable acid can be used in the method of the present invention.Representative acids include organic acids such as carboxylic acids andhalogenated carboxylic acids, mineral acids such as sulfuric acid,sulfonic acids such as methanesulfonic acid, and others. The acids canbe strong acids, i.e., acids having a pKa less than about 1. In someembodiments, the acid can be a strong acid. In some embodiments, theacid can be hydrofluoric acid, hydrochloric acid, hydrobromic acid,hypochloric acid, perchloric acid, sulfuric acid, nitric acid,phosphoric acid, hexafluorophosphoric acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonicacid, fluoroacetic acid, or trifluoroacetic acid. In some embodiments,the acid can be sulfuric acid or trifluoroacetic acid. In someembodiments, the acid can be sulfuric acid. In some embodiments, theacid can be trifluoroacetic acid.

In some embodiments, the method includes forming the reaction mixturecomprising levulinic acid, trifluoroacetic acid, and hydrogen peroxide,and heating the reaction mixture at a temperature of from about 50° C.to about 100° C., thereby preparing succinic acid.

Any suitable solvent can be used in the methods of the invention.Suitable solvents include, but are not limited to, diethyl ether,diisopropyl ether, ethyl acetate, pentane, hexane, heptane, cyclohexane,benzene, toluene, chloroform, dichloromethane, carbon tetrachloride,1,2-dichloroethane, 1,1-dichloroethane, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, N-methyl 2-pyrrolidone, aceticacid, trifluoroacetic acid, trichloroacetic acid, methyl ethyl ketone,methyl isobutylketone, acetonitrile, propionitrile, 1,4-dioxane,sulfolane, 1,2-dimethyoxyethane, and combinations thereof.

Any suitable reaction time can be used in the methods of the invention.In general, reactions are allowed to run for a time sufficient forconsumption of the starting material and conversion to the desiredproduct, or until conversion of the starting material comes to a stop.Reactions are typically allowed to run for any amount of time rangingfrom a few minutes to several hours. Reactions can be run, for example,for anywhere between 5 minutes and 48 hours. Reactions can be run forabout 5 minutes, or about 10, 15, 20, 30, 45, 60, or more minutes.Reactions can be run for about 1, 2, 3, 4, 5, or more hours.

B. Preparation of 3-Hydroxypropanoic Acid

As discussed above, hydrogen peroxide is identified as a reagent ofgreat potential for the oxidation of LA due to its well-knownBaeyer-Villiger-type mechanism of action, that could in fact lead eitherto SA or HPA, depending on which group undergoes migration. Running thereaction under acidic conditions favors methyl group migration to giveSA in good yield. Surprisingly, the selectivity of the migration couldbe controlled by switching the pH of the medium from acidic to basic.Thus, LA was dissolved in 30% aq. H₂O₂ and potassium hydroxide wasadded. The reaction was heated to 115° C. and further portions of baseand H₂O₂ were added over the course of about 10 minutes. Unlike the samereaction in acid, rapid evolution of oxygen was observed at eachaddition. The mixture was allowed to stir undisturbed for a period oftime before a final portion of H₂O₂ and KOH was added. The entireprocess was complete within about 90 minutes. Quantitative analysis byNMR using an internal standard showed that HPA was being produced in 47%yield. The mass balance consisted of acetic acid (89%), formic acid(29%), and methanol (9%). A volatiles trap further detected traces ofacetone (ca. 1%). Running the same reaction at a lower temperature (60°C.) reduces the yield of HPA (22%) but increases the yield of acetone(10%).

The range of observed products indicated that processes other than thoseshown in Scheme 3 are operative in this chemistry. Specifically, thefact that more acetic acid is produced than HPA demonstrates that morethan one route to this product is available. The most likely scenario isoxidation of the enolate of LA to give 3-hydroxylevulinic acid (3HLA)(Scheme 4). Retro aldol cleavage of 3HLA yields acetate andmethylglyoxal (MG). Baeyer-Villiger oxidation of MG is favored at theketo group, since the aldehyde exists mainly in the form of a hydrate.Methyl migration leads to the glyoxylic acid ester, which hydrolyzes toglyoxylate (GA), which itself breaks down on further oxidation toformate and CO₂. An alternative pathway involving dehydration of 3HLAand rehydration to 2-hydroxylevulinic acid (2HLA) can also be proposed.Retro aldol of 2HLA yields acetone and again GA. To test thesemechanistic postulates, an independent sample of MG was submitted to thereaction conditions and in fact, only formate and methanol were observedin the NMR spectrum. A sample of GA produced only formate under the sameconditions. The observation of methanol may also derive fromBaeyer-Villiger oxidation of acetone and subsequent hydrolysis of themethyl acetate product.

A by-product was observed in the reaction conducted at 60° C. which wasnot detected in the higher temperature process. It appeared similar toHPA but showed a greater downfield shift of the methylene group adjacentto oxygen in the ¹H NMR. This was the corresponding hydroperoxide, i.e.3-(hydroperoxy)propanoic acid (HPPA), confirmed by iodometric titrationand by derivatization with MeI and Ag₂O to give methyl 3-(methylperoxy)propanoate. The yield of HPPA at 60° C. was low, but further reducingthe reaction temperature appeared to favor this product. Ultimately, itwas found that carrying out the reaction between 0° C. and roomtemperature over the course of about 6 h resulted in the production ofHPPA in 82% yield by ¹H NMR integration, which was confirmed byisolation of the product in 80% yield. The expected, equivalent yield ofacetic acid (80%) was also observed, alongside HPA (5%) and formic acid(4%). To avoid distillation of water in the isolation of HPPA, theproduct was isolated by continuous extraction with ether. Conversion ofHPPA to HPA by O—O bond hydrogenolysis over Pd/C was facile andquantitative, and hence this approach to HPA is considered to be themethod of choice.

Two pathways for the generation of HPPA are proposed, one or both ofwhich may be operative. First, it is possible that, instead ofhydrolysis of the acetate, elimination to an acrylate intermediate mayoccur as shown in Scheme 5. The higher nucleophilicity of hydroperoxideanion may explain the selectivity for HPPA over HPA in this lowertemperature reaction. Alternatively, attack on the acetate carbonyl byhydroperoxide anion would give a tetrahedral intermediate which couldrearrange as shown to give HPPA and acetate.

The present invention provides a new concept for the derivation of3-hydroxypropanoic acid from biomass. The process is fullychemical-catalytic, comparatively fast (vs. fermentation), operatesunder mild conditions, and gives HPA in high yield (>80% overall fromLA). The mass balance of the reaction consists mainly of acetic acid,which is itself a useful commodity chemical. Since LA can be derivedfrom raw cellulosic biomass in high yield, this practical, two-stepmethod appears highly attractive for the industrial production ofrenewable acrylate derivatives, other C₃ chemicals (e.g.1,3-propanediol, malonic acid), and the HPA homopolymer, whilecompletely avoiding fermentation pathways.

In some embodiments, the present invention provides a method ofpreparing 3-hydroxypropanoic acid. The compound 3-hydroxypropanoic acidhas the following formula:

In some embodiments, the present invention provides a method ofpreparing 3-hydroxypropanoic acid, including forming a reaction mixturecomprising levulinic acid, an oxidant, and a base, under conditionssuitable to form the 3-hydroxypropanoic acid. In some embodiments, themethod includes forming the reaction mixture comprising levulinic acid,the oxidant, and a base, under conditions suitable to form the3-hydroxypropanoic acid.

Bases useful in the method of making 3-hydroxypropanoic acid includestrong bases with conjugate acids having a pKa greater than about 13.Representative bases include, but are not limited to, lithium hydroxide,sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesiumhydroxide, magnesium hydroxide, strontium hydroxide, barium hydroxide,and others. In some embodiments, the strong base can be sodium hydroxideor potassium hydroxide. In some embodiments, the strong base can bepotassium hydroxide.

The method of forming 3-hydroxypropanoic acid can be conducted at anysuitable temperature. In general, reactions are conducted attemperatures ranging between about 0° C. and about 200° C. A reactioncan be conducted, for example, at from about 25° C. to about 200° C., orfrom about 50° C. to about 200° C., or from about 75° C. to about 200°C., or from about 100° C. to about 150° C. A reaction can be conductedat about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, or about 155° C.In some embodiments, the temperature can be about 115° C.

In some embodiments, the reaction mixture can be at a temperaturebetween about 75° C. and about 200° C. In some embodiments, the reactionmixture can be at a temperature between about 100° C. and about 150° C.In some embodiments, the method of making 3-hydroxypropanoic acidincludes forming the reaction mixture comprising levulinic acid,hydrogen peroxide, and potassium hydroxide, wherein the reaction mixtureis at a temperature between about 100° C. and about 150° C., therebyforming the 3-hydroxypropanoic acid.

Alternatively, the temperature of the reaction mixture for preparing the3-hydroxypropanoic acid can be between about 0° C. and about 50° C. Areaction can be conducted, for example, at from about 0° C. to about 50°C., or from about 0° C. to about 30° C., or from about 20° C. to about30° C., or from about 0° C. to about 25° C. A reaction can be conductedat about 0, 5, 10, 25, 30, 35, 40, 45, or about 50° C. In someembodiments, the temperature can be about room temperature. In someembodiments, the temperature can be less than about room temperature.

In some embodiments, the reaction mixture can be at a temperaturebetween about 0° C. and about 50° C. such that the product of theforming step is 3-(hydroperoxy)propanoic acid, and the method alsoincludes forming a second reaction mixture comprising the3-(hydroperoxy)propanoic acid and a hydrogenation agent, underconditions suitable to form the 3-hydroxypropanoic acid. The compound3-(hydroperoxy)propanoic acid has the following structure:

Any suitable hydrogenation agent can be used in the method of reducing3-(hydroperoxy)propanoic acid to form 3-hydroxypropanoic acid.Hydrogenation agents are preferably non-nucleophilic. Representativehydrogenation agents include, but are not limited to, palladium oncarbon. In some embodiments, the hydrogenation agent can be palladium oncarbon. In some embodiments, the second reaction mixture also includeshydrogen gas. In some embodiments, the hydrogenation agent can bepalladium on carbon and hydrogen gas. In some embodiments, the method offorming 3-hydroxypropanoic acid includes forming the reaction mixturecomprising levulinic acid, hydrogen peroxide, and potassium hydroxide,wherein the reaction mixture is at about room temperature, therebypreparing 3-(hydroperoxy)propanoic acid; and forming the second reactioncomprising the 3-(hydroperoxy)propanoic acid, hydrogen gas and palladiumon carbon, under conditions suitable to form the 3-hydroxypropanoicacid.

Other steps are useful in the method of making 3-hydroxypropanoic acid.For example, the reaction mixture containing 3-(hydroperoxy)propanoicacid can be neutralized using acid, and then the3-(hydroperoxy)propanoic acid can be isolated via extraction. In someembodiments, the method of preparing 3-hydroxypropanoic acid includes,prior to the second forming step, contacting the reaction mixture withan acid such that the pH of the reaction mixture is less than 7.0, andisolating the 3-(hydroperoxy)propanoic acid via extraction.

Any suitable acid can be used in the contacting step to neutralize thereaction mixture. Representative acids include, but are not limited to,formic acid, acetic acid, citric acid, lactic acid, oxalic acid,trifluoroacetic acid, hydrofluoric acid, hydrochloric acid, hydrobromiceacid, hypochlorous acid, perchloric acid, sulfuric acid, nitric acid,phosphoric acid, chromic acid, boric acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, triflouromethanesulfonicacid, or camphorsulfonic acid. In some embodiments, the acid can behydrofluoric acid, hydrochloric acid, hydrobromic acid, hypochloricacid, sulfuric acid, nitric acid, phosphoric acid, hexafluorophosphoricacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, trifluoromethanesulfonic acid, fluoroacetic acid, ortrifluoroacetic acid. In some embodiments, the acid can be hydrochloricacid.

Any suitable amount of acid can be used to reduce the pH of the reactionmixture containing the 3-(hydroperoxy)propanoic acid. For example, thepH of the reaction mixture containing the 3-(hydroperoxy)propanoic acidcan be reduced to a pH less than 7.0, 6.0, 5.0, 4.0, or less than about3.0. In some embodiments, the pH of the reaction mixture containing the3-(hydroperoxy)propanoic acid is less than 7.0.

In some embodiments, the 3-(hydroperoxy)propanoic acid can be extractedby any suitable method. For example, the 3-(hydroperoxy)propanoic acidcan be extracted via continuous extraction using ether as the extractionsolvent.

In some embodiments, the method of preparing 3-hydroxypropanoic acidincludes forming the reaction mixture comprising levulinic acid,hydrogen peroxide, and potassium hydroxide, wherein the reaction mixtureis at about room temperature, thereby preparing 3-(hydroperoxy)propanoicacid, contacting the reaction mixture with hydrochloric acid such thatthe pH of the reaction mixture is less than 7.0, isolating the3-(hydroperoxy)propanoic acid via extraction, and forming the secondreaction comprising the 3-(hydroperoxy)propanoic acid, hydrogen andpalladium on carbon, under conditions suitable to form the3-hydroxypropanoic acid.

Any suitable reaction time can be used in the method of the invention.In general, reactions are allowed to run for a time sufficient forconsumption of the starting material and conversion to the desiredproduct, or until conversion of the starting material comes to a stop.Reactions are typically allowed to run for any amount of time rangingfrom a few minutes to several hours. Reactions can be run, for example,for anywhere between 5 minutes and 48 hours. Reactions can be run forabout 5 minutes, or about 10, 15, 20, 30, 45, 60, or more minutes.Reactions can be run for about 1, 2, 3, 4, 5, or more hours.

IV. Examples

Materials and methods. Levulinic acid (98%), sulfuric acid (98%), sodiumthiosulfate, potassium iodide, palladium on activated carbon (10 wt %),methyl iodide, and silver oxide were all purchased from Sigma Aldrichand used as received. Trifluoroacetic acid (99%), diethyl ether, anddichloromethane were purchased from Fischer Scientific. Hydrogenperoxide (30% aq) was purchased from Macron Chemicals. Hydrochloric acid(37% aq) was purchased from EMD Chemicals. Potassium hydroxide(technical, 87%) was purchased from Fisher Scientific.

Example 1 Oxidation of Levulinic Acid to Succinic Acid with HydrogenPeroxide in 3M Sulfuric Acid

Levulinic acid (2.00 g, 17.2 mmol) was dissolved in 3M H₂SO₄ (20 mL) and30% aq H₂O₂ (8 mL) was carefully added. The colorless solution wasplaced in an oil bath at 90° C. and stirred for 3.5 h. Additional 30% aqH₂O₂ (2.0 mL) was added, followed 20 min later by another aliquot of 30%aq H₂O₂ (2.0 mL). After 20 min the mixture was cooled to RT and ameasured quantity of 1,4-dioxane was added as an internal standard. The¹H NMR spectrum was measured and the yields were determined as follows:succinic acid (48%), acetic acid (50%), formic acid (24%) and methanol(17%).

Example 2 Oxidation of LA by Hydrogen Peroxide in TFA

Levulinic acid (2.00 g, 17.2 mmol) was dissolved in TFA (40 mL) and 30%aq H₂O₂ (2.0 mL) was carefully added. The flask was mounted with awater-cooled condenser and −78° C. volatiles trap, and the colorlessmixture was placed in an oil bath at 90° C. and stirred for 20 min.Additional 30% aq H₂O₂ (8.0 mL) was added portionwise at a rate of 2 mLevery 20 min. The reaction was allowed to stir a further 20 min afterthe final addition, at which point the LA had been completely consumedas indicated by ¹H NMR analysis. The mixture was cooled to roomtemperature and a measured amount of 1,4-dioxane was added as aninternal standard. The ¹H NMR spectrum was measured and the yields weredetermined as follows: succinic acid (62%), acetic acid (43%),3-hydroxypropanoic acid (9%), and formic acid (45%). Methyltrifluoroacetate (45%) was obtained in the cold trap. The volatiles wereevaporated to give a white solid which was triturated with Et₂O (2×2 mL)to give succinic acid (1.22 g, 60%). ¹H NMR δ: 2.64 (4H). ¹³C NMR δ:176.9, 28.58.

Example 3 Scale-Up of the Oxidation of LA by Hydrogen Peroxide in TFA

Levulinic acid (10.00 g, 86.12 mmol) was dissolved in TFA (200 mL) and30% aq H₂O₂ (10 mL) was carefully added. The flask was mounted with awater-cooled condenser and −78° C. volatiles trap, and the colorlessmixture was placed in an oil bath at 90° C. and stirred for 20 min.Additional 30% aq H₂O₂ (40 mL) was added portionwise at a rate of 10 mLevery 20 min. The reaction was allowed to stir a further 30 min afterthe final addition, at which point the LA had been completely consumedas indicated by ¹H NMR analysis. The mixture was cooled to roomtemperature and a measured amount of 1,4-dioxane was added as aninternal standard. The volatiles were evaporated under reduced pressureto give a white solid. The crude product was triturated with 1:1Et₂O/DCM (3×6 mL) to give succinic acid (6.00 g, 59%). In the cold trap,methyl trifluoroacetate was isolated as a colorless oil (4.40 g, 40%).

Example 4 Direct Oxidation of Levulinic Acid to 3-Hydroxypropanoic Acid(HPA) with Hydrogen Peroxide

Levulinic acid (2.0 g, 17.3 mmol) was dissolved in 30% aq H₂O₂ (6 mL) at0° C. and KOH (1.0 g) was added portionwise. The flask was then equippedwith a condenser and a volatiles trap and placed in an oil bathpreheated to 115° C. After 10 min, additional KOH (1.0 g) was addedportionwise followed by 30% aq H₂O₂ (1 mL). Once gas evolution hadceased (1-2 min), additional KOH (1.0 g) was added portionwise followedslowly by 30% aq H₂O₂ (7 mL). Once gas evolution had again ceased (1-2min), additional KOH (1.0 g) was added portionwise followed slowly by30% aq. H₂O₂ (6 mL). The reaction mixture was then allowed to stir at115° C. for 50 min. Finally, additional KOH (0.5 g) was addedportionwise followed slowly by 30% aq H₂O₂ (4 mL). The solution wasstirred for an additional 10 min then allowed to cool to roomtemperature. A measured amount of 1,4-dioxane was added as internalstandard and the reaction mixture was analyzed by ¹H NMR. The productyields determined by this method were HPA (47%), acetic acid (89%),formic acid (29%), and methanol (9%). Acetone (ca. 1%) was collectedfrom the volatiles trap. The mixture was cooled in an ice bath andacidified to pH 3-4 using conc HCl. The volatiles were evaporated underreduced pressure to give a white solid. The HPA product was extractedfrom this mixture using ether (3×50 mL). After the evaporation of thesolvent, HPA was obtained as a colorless oil (700 mg, 45%). ¹H NMR (600MHz, D₂O) δ 3.83 (t, J=6.0 Hz, 2H), 2.59 (t, J=6.0 Hz, 2H); ¹³C NMR (150MHz, D₂O) δ 175.9, 71.9, 32.8.

Example 5 Preparation of 3-Hydroxypropanoic Acid from Levulinic Acid

This example describes the preparation of 3-hydroxypropanoic acid fromlevulinic acid, via 3-(hydroperoxy)propanoic acid.

Oxidation of levulinic acid to 3-(hydroperoxy)propanoic acid withhydrogen peroxide: Levulinic acid (4.00 g, 34.5 mmol) was dissolved in30% aq H₂O₂ (24 mL) at 0° C. To the resulting solution was addeddropwise with stirring 5.2 M aq KOH (28.8 mL, 150 mmol). The ice bathwas replaced by a water bath and the mixture was allowed to stir for 1.5h. The water bath was then removed and the mixture was allowed to stiran additional 2.5 h. Finally, another portion of 30% aq H₂O₂ (8.0 mL)was added. The solution was allowed to stir until NMR indicated fullconversion of the levulinic acid, ca. 2 h after the final addition ofH₂O₂. The mixture was cooled in an ice bath and acidified to pH 3-4 withconc HCl. A measured amount of 1,4-dioxane was added as internalstandard and the reaction mixture was analyzed by ¹H NMR. The productyields determined by this method were 3-(hydroperoxy)propanoic acid(82%), acetic acid (80%), 3-hydroxypropanoic acid (5%) and formic acid(4%). The 3-(hydroperoxy)propanoic acid product could be isolated bycontinuous extraction (5 h) of the acidified reaction mixture usingether as the extraction solvent. After the evaporation of the volatiles,3-(hydroperoxy)propanoic acid was obtained as a colorless oil (2.91 g,80%) along with a small quantity of 3-hydroxypropanoic acid. ¹H NMR (300MHz, D₂O) δ 4.18 (t, J=5.9 Hz, 2H), 2.67 (t, J=5.9 Hz, 2H); ¹³C NMR (75MHz, D₂O) δ 175.9, 71.9, 32.8.

Hydrogenation of 3-(hydroperoxy)propanoic acid to 3-hydroxypropanoicacid: The above-produced 3-(hydroperoxy) propanoic acid (2.90 g, 27.4mmol) was dissolved in 30 mL of methanol. Palladium on activated carbon(10 wt % Pd, 30 mg) was added and the mixture was carefully evacuatedand then backfilled with hydrogen three times. The reaction flask waspressurized to 3.8 atm hydrogen and shaken for 40 min. The mixture wasfiltered through a short plug of Celite, which was further rinsed withmethanol (30 mL). The solvent was evaporated to give 3-hydroxypropanoicacid (HPA) as a colorless oil (2.48 g, 100%). ¹H NMR (600 MHz, D₂O) δ3.83 (t, J=6.0 Hz, 2H), 2.59 (t, J=6.0 Hz, 2H); ¹³C NMR (150 MHz, D₂O) δ175.9, 71.9, 32.8.

Example 6 Derivatization of 3-(hydroperoxy)propanoic Acid

A mixture of 3-(hydroperoxy)propanoic acid (410 mg, 3.9 mmol), silveroxide (2.5 g, 11 mmol), methyl iodide (1.5 g, 11 mmol) and DCM (15 mL)was stirred in the dark for 16 h at room temperature. The reaction wasfiltered through a short plug of Celite and the solvent was evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel to give methyl 3-(methylperoxy)propanoateas a colorless oil (150 mg, 29%). ¹H NMR (600 MHz, CDCl₃) δ 4.23 (t,J=6.2 Hz, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 2.64 (t, J=6.2 Hz, 2H); ¹³CNMR (150 MHz, CDCl₃) δ 171.6, 69.4, 62.3, 51.8, 33.3.

Example 7 Iodometric Titration of 3-(hydroperoxy)propanoic Acid

A sample of 3-(hydroperoxy)propanoic acid in EtOAc was filtered througha plug of silica gel. The solvent was evaporated and the residue wasdissolved in D₂O. A measured amount of 1,4-dioxane was added as internalstandard. The quantity of 3-(hydroperoxy)propanoic acid was determinedto be 1.61 mmol by ¹H NMR analysis. To this solution was added potassiumiodide (1.07 g, 6.44 mmol) and 1.0 M aq HCl (20 mL). The mixture wasstirred in the dark for 20 min. It was found that 32.4 mL of 0.100 Msodium thiosulfate solution (3.24 mmol) was required to titrate thegenerated iodine to a colorless endpoint with a starch indicator.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference. Where a conflictexists between the instant application and a reference provided herein,the instant application shall dominate.

What is claimed is:
 1. A method of preparing a carboxylic acid, whereinthe carboxylic acid is 3-hydroxypropanoic acid, comprising: forming areaction mixture comprising levulinic acid, a peroxide oxidant, and astrong base, under conditions suitable to prepare the carboxylic acid.2. The method of claim 1, wherein the peroxide oxidant is hydrogenperoxide.
 3. The method of claim 2, wherein the reaction mixture is freeof an oxidizing metal catalyst.
 4. The method of claim 1, wherein thestrong base is selected from the group consisting of sodium hydroxideand potassium hydroxide.
 5. The method of claim 1, wherein the reactionmixture is at a temperature between about 75° C. and about 200° C. 6.The method of claim 1, wherein the peroxide oxidant is hydrogen peroxideand the strong base is potassium hydroxide, and wherein the methodcomprises: forming the reaction mixture comprising levulinic acid,hydrogen peroxide, and potassium hydroxide, wherein the reaction mixtureis at a temperature between about 100° C. and about 150° C., therebyforming the 3-hydroxypropanoic acid.
 7. A method of preparing acarboxylic acid, wherein the carboxylic is 3-hydroxypropanoic acid,comprising: forming a reaction mixture comprising levulinic acid, aperoxide oxidant, and a strong base, wherein the reaction mixture is ata temperature between about 0° C. and about 50° C. such that the productof the forming step is 3-(hydroperoxy)propanoic acid, and the methodfurther comprises: forming a second reaction mixture comprising the3-(hydroperoxy)propanoic acid and a hydrogenation agent, underconditions suitable to form the 3-hydroxypropanoic acid.
 8. The methodof claim 7, wherein the hydrogenation agent is hydrogen gas andpalladium on carbon.
 9. The method of claim 7, wherein the peroxideoxidant is hydrogen peroxide, the strong base is potassium hydroxide,and the hydrogenation agent is hydrogen gas and palladium on carbon, andwherein the method comprises: forming the reaction mixture comprisinglevulinic acid, hydrogen peroxide, and potassium hydroxide, wherein thereaction mixture is at about room temperature, thereby preparing3-(hydroperoxy)propanoic acid; and forming the second reaction mixturecomprising the 3-(hydroperoxy)propanoic acid, hydrogen gas and palladiumon carbon, under conditions suitable to form the 3-hydroxypropanoicacid.
 10. The method of claim 7, further comprising prior to the secondforming step: contacting the reaction mixture with an acid such that thepH of the reaction mixture is less than 7.0; and isolating the3-(hydroperoxy)propanoic acid via extraction.
 11. The method of claim10, wherein the acid is selected from the group consisting ofhydrofluoric acid, hydrochloric acid, hydrobromic acid, hypochloricacid, sulfuric acid, nitric acid, phosphoric acid, hexafluorophosphoricacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, trifluoromethanesulfonic acid, fluoroacetic acid, andtrifluoroacetic acid.
 12. The method of claim 7, wherein the peroxideoxidant is hydrogen peroxide, the strong base is potassium hydroxide,and the hydrogenation agent is hydrogen gas and palladium on carbon, andwherein the method comprises: forming the reaction mixture comprisinglevulinic acid, hydrogen peroxide, and potassium hydroxide, wherein thereaction mixture is at about room temperature, thereby preparing3-(hydroperoxy)propanoic acid; contacting the reaction mixture withhydrochloric acid such that the pH of the reaction mixture is less than7.0; isolating the 3-(hydroperoxy)propanoic acid via extraction; andforming the second reaction mixture comprising the3-(hydroperoxy)propanoic acid, hydrogen gas and palladium on carbon,under conditions suitable to form the 3-hydroxypropanoic acid.